Environmental temperature variations can be extreme. Many species, including mammals, are homeothermic, and tightly regulate internal temperatures for efficient metabolism and survival. To regulate temperature homeostasis, we have evolved various mechanisms to sense temperature. Perhaps best characterized among these is the thermosensitivity of somatosensory neurons - specialized to sense environmental changes in temperature as reflected in peripheral tissues such as the skin. A subset of Transient Receptor Potential (TRP) family of ion channels dubbed thermoTRPs are shown to be activated by distinct temperatures, are expressed in somatosensory neurons, and are required for peripheral thermosensation. Interestingly, at least two of these thermoTRPs are also expressed in keratinocytes, implicating skin cells in thermosensation. Many of the thermoTRP knockout mice have thermosensory deficits. However, recent unpublished data from our lab suggests that thermoTRPs are unlikely to explain all of the thermosensory capability of the somatosensory system. Skin cells experience wide temperature variations and contribute to inflammation and heat-induced vasodilation, in addition to potentially being involved in thermosensation. Furthermore, the molecular mechanism of thermosensitivity of other tissues/cells is not currently known. We have recently shown that STIM1/Orai1 ion channel complex is acutely thermosensitive. This proposal will build on these preliminary data and pursue the general hypothesis that these temperature- sensitive ion channels play an essential role in sensing temperature.